Methods and Results—Using adult Cav1-/- mice, we revealed a marked reduction in the left ventricular (LV) conduction velocity in the absence of myocardial Cav1, which is accompanied with increased inducibility of ventricular arrhythmias. Further studies demonstrated that loss of Cav1 leads to the activation of cSrc tyrosine kinase, resulting in the downregulation of connexin 43 (Cx43) and subsequent electrical abnormalities. Pharmacological inhibition of cSrc mitigates Cx43 downregulation, slow conduction and arrhythmia inducibility in Cav1-/- animals. Using a transgenic mouse model with cardiac-specific overexpression of angiotensin converting enzyme (ACE8/8), we demonstrated that, upon enhanced cardiac RAS activity, Cav1 dissociated from cSrc because of increased Cav1 S-nitrosation (SNO) at Cys156, leading to c-Src activation, Cx43 reduction, impaired gap junction function, and subsequent increase in the propensity for ventricular arrhythmias and sudden cardiac death. RAS-induced Cav1 SNO was associated with increased Cav1-eNOS binding in response to increased mitochondrial reactive oxidative species (ROS) generation.

Conclusions—The present studies reveal the critical role of Cav1 in modulating cSrc activation, gap junction remodeling and ventricular arrhythmias. These data provide a mechanistic explanation for the observed genetic link between Cav1 and cardiac arrhythmias in humans and suggest that targeted regulation of Cav1 may reduce arrhythmic risk in cardiac diseases associated with RAS activation.